Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation for Solid Cancer.

We wanted to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) may result in long-term survival in patients with solid cancer. HSCT was performed in 61 patients with solid cancer: metastatic renal carcinoma (n = 22), cholangiocarcinoma (n = 17), colon carcinoma (n = 15), prostate cancer (n = 3), pancreatic adenocarcinoma (n = 3), or breast cancer (n = 1). Liver transplantation was performed for tumor debulking in 18 patients. Median age was 56 years (range, 28 to 77). Donors were either HLA-identical siblings (n = 29) or unrelated (n = 32). Conditioning was nonmyeloablative (n = 23), reduced (n = 36), or myeloablative (n = 2). Graft failure occurred in 13 patients (21%). The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 47%, and that of chronic GVHD was 32%. Treatment-related mortality was 21%. At 5 years cancer-related mortality was 63%. Currently, 6 patients are alive, 2 with renal cell carcinoma, 1 with cholangiocarcinoma, and 3 with pancreatic carcinoma. Eight-year survival was 12%. Risk factors for mortality were nonmyeloablative conditioning (HR, 2.95; P < .001), absence of chronic GVHD (HR, 3.57; P < .001), acute GVHD of grades II to IV (HR, 2.90; P = .002), and HLA-identical transplant (HR, 5.00; P = .03). With none of these risk factors, survival at 6 years was 50% (n = 6). Long-term survival can be achieved in some patients with solid cancer after HSCT.

A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer.

BACKGROUND: AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naïve patients with inoperable pancreatic carcinoma. PATIENTS AND METHODS: AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of four × four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated. RESULTS: Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 µM. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up. CONCLUSION: Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients.

HLA, GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT.

UNLABELLED: Hepatic dysfunction is common after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to determine the risk factors, frequency, and outcome of hepatic complications post-HSCT in children. Two hundred and thirty-seven cases of allogeneic HSCT in children were included. Data on biochemical liver function at start of HSCT, at +1, +3, +6, and +9 months, and at each subsequent yearly follow-up were extracted. Patients were stratified into groups with hepatocellular (none and mild, and moderate to severe) and hepatobiliary (none and present) dysfunction. Statistical analysis included variables such as diagnosis, age, conditioning regimen, and HLA type. RESULTS: One hundred and fifty-six (66%) patients displayed hepatocellular dysfunction post-HSCT. In most cases transient, but 32% had a persistent abnormality three yr post-HSCT. Risk factors were chronic GVHD (OR 4.20, p = 0.003) and donor HLA-A*01 (OR 2.97, p = 0.02). HLA-DQB1*03 decreased the risk (OR 0.35, p = 0.02). Hepatobiliary dysfunction was less frequent (12%) but carried a poor prognosis. aGVHD grade II-IV (OR 2.7, p = 0.02) and long-term TPN (OR 3.25, p = 0.01) increased the risk. CONCLUSION: GVHD is an important risk factor for liver dysfunction post-HSCT. Specific HLA types may also contribute as a risk factor, while others seem to have a protective effect.

Photochemotherapy of Cutaneous Graft-versus-Host Disease May Reduce Concomitant Visceral Disease.

BACKGROUND: Photochemotherapy may be used to treat cutaneous graft-versus-host disease (GvHD). Animal models show that in the days after photochemotherapy and antigen provocation, cells with an antigen-specific suppressive phenotype are elicited in the lymphoid organs. In GvHD, host antigens are present not only in the skin treated by photochemotherapy but also in the visceral tissues. OBJECTIVE: The aim of this paper was to evaluate the effect on visceral acute GvHD (aGvHD) of photochemotherapy of the skin. METHODS: We retrospectively evaluated 33 patients with aGvHD of the skin, the liver, and/or the gastrointestinal tract treated with photochemotherapy for their aGvHD of the skin and did a long-term follow-up of 10 years on survival. RESULTS: The complete response (CR) to photochemotherapy was 39%, the complete and partial response was 64% and the 6-month survival was 64%. Total body irradiation (TBI) before hematopoietic stem cell transplantation predisposed for CR of aGvHD of the liver and the gastrointestinal tract (p = 0.045). In the TBI group, the accumulated dose (numbers of treatments) for CR of visceral aGvHD increased with the body surface area affected by disease, from 8 (min-max: 5-14) for skin disease stage 1 to 10.5 (6-33) for stage 2 and 13 (11-21) for stage 3 (p = 0.04). Skin disease stage 1 showed a trend to be associated with CR in visceral disease at 28, 56, and 100 days (p = 0.07). Overall CR in visceral disease predicted a better 10-year overall survival (p = 0.0036). Finally, after TBI aGvHD of the gastrointestinal tract without anti-thymocyte globulin (ATG), clearance of T cells and dendritic cells responded better than aGvHD of the liver and aGvHD of the gastrointestinal tract with ATG (p = 0.01). CONCLUSION: Photochemotherapy after ionizing irradiation regulates the cell-mediated immunity in the viscera, and the systemic efficacy increases when the skin itself is less affected by disease. ATG modulates the regulatory effect of the gastrointestinal tract.

Hypogammaglobulinemia in children after allogeneic hematopoietic stem cell transplantation: a cytokine mediated immunoglobulin isotype class switch arrest?

BACKGROUND: Hypogammaglobulinemia (hypo-IgG) is common early post-HSCT in children, occasionally necessitating long-term immunoglobulin (Ig) G replacement therapy. IgG replacement may not reduce mortality, although infectious complications are decreased PROCEDURE: Clinical data and samples from 86 children were analyzed retrospectively with the aim to identify risk factors for developing long-term hypo-IgG (i.e., requiring ≥ 3 months IgG replacement) post-HSCT and studying the underlying biology. Laboratory studies covered serum cytokines, IGHG2 genotyping and routine laboratory investigations. Results were analyzed statistically. RESULTS: Forty-eight percent of the children developed long-term hypo-IgG. These children were younger (<5 years) and had higher acute GvHD incidence, but had better overall survival (88% vs. 69%, P = 0.036). Significantly lower Ig levels post-HSCT but equal immune cell recovery were seen in patients with long-term hypo-IgG compared with those of transient or no hypo-IgG. Pre-HSCT IL-6 and -7 and post-HSCT BAFF and APRIL levels were significantly higher in the long-term hypo-IgG group. CONCLUSIONS: Findings suggests an unfavorable cytokine milieu for graft-derived immune recovery, possibly inducing Ig isotype class switch arrest. Younger age, acute GvHD, and higher pre-HSCT IL-6 levels were identified as significant risk factors for long-term hypo-IgG. Long-term hypo-IgG post-HSCT does not need to be unfavorable and could be an effect of deteriorated cytokine signaling.

Vitamin d levels affect outcome in pediatric hematopoietic stem cell transplantation.

The importance of vitamin D in immunologic processes has recently emerged, but whether it has any impact on the course of allogeneic hematopoietic stem cell transplantation (HSCT) has not been determined. Reports indicate that HSCT recipients, particularly children, often suffer from vitamin D deficiency. This study investigated the role of vitamin D in 123 children undergoing HSCT from 2004 to 2011. Vitamin D (ie, serum calcidiol) was analyzed in collected cryostored samples. Patients were grouped according to pre-HSCT calcidiol level: insufficient (<50 nm/L, n = 38) and sufficient (≥50 nm/L, n = 85). Older children who underwent transplants from January through June and children of Middle Eastern or African origin were more commonly found in the insufficient group. Acute grades II to IV graft-versus-host disease occurred more frequently in the vitamin D sufficient group (47% versus 30%, P = .05), whereas no difference was demonstrated for chronic graft-versus-host disease. The neutrophil granulocytes rose significantly faster in the vitamin D sufficient group. No difference in lymphocyte counts, immunoglobulin levels, or infectious disease burden during the first year post-HSCT were observed. Among children with malignancies, overall survival was significantly better in the sufficient group (87% versus 50%, P = .01). In addition, rejection (0% versus 11%, P = .06) and relapse (4% versus 33%, P = .03) rates were lower in patients with sufficient vitamin D levels. To conclude, vitamin D may have an important impact on the outcome of pediatric HSCT, particularly in patients with malignant disease. Further studies investigating whether vitamin D acts as an immunomodulator or is merely a surrogate marker of patient health or nutritional status are warranted.

Many days at home during neutropenia after allogeneic hematopoietic stem cell transplantation correlates with low incidence of acute graft-versus-host disease.

Patients are isolated in the hospital during the neutropenic phase after allogeneic hematopoietic stem cell transplantation. We challenged this by allowing patients to be treated at home. A nurse from the unit visited and checked the patient. One hundred forty-six patients treated at home were compared with matched hospital control subjects. Oral intake was intensified from September 2006 and improved (P = .002). We compared 4 groups: home care and control subjects before and after September 2006. The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 15% in the "old" home care group, which was significantly lower than that of 32% to 44% in the other groups (P < .03). Transplantation-related mortality, chronic GVHD, and relapse were similar in the groups. The "new" home care patients spent fewer days at home (P = .002). In multivariate analysis, GVHD of grades 0 to I was associated with home care (hazard ratio [HR], 2.46; P = .02) and with days spent at home (HR, .92; P = .005) but not with oral nutrition (HR, .98; P = .13). Five-year survival was 61% in the home care group as compared with 49% in the control subjects (P = .07). Home care is safe. Home care and many days spent at home were correlated with a low risk of acute GVHD.

Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study.

We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.

GVHD prophylaxis using low-dose cyclosporine improves survival in leukaemic recipients of HLA-identical sibling transplants.

Graft-versus-host disease (GVHD) prophylaxis of short duration (6 months) with low-dose cyclosporine A (CsA) starting at 1 mg/kg per day i.v. and four doses of methotrexate (MTX) were given to 171 consecutive leukaemic recipients of HLA-identical sibling transplants. In contrast, apart from MTX, retrospective controls received high-dose CsA, starting at 5-7.5 mg/kg per day i.v. and discontinued 1 yr post-transplant. In the low-dose CsA group, the probability of acute GVHD grades I-II (70% vs. 53%, P < 0.01), and chronic GVHD were increased (58% vs. 25%, P < 0.01), whereas the incidences of acute GVHD grades III-IV (9% vs. 5%, P = 0.62), and non-relapse mortality (20% vs. 22%, P = 0.58) were similar. Moreover, the probability of relapse was decreased (31% vs. 54%, P < 0.01), and both relapse-free (56% vs. 38%, P = 0.04) and overall survival (61% vs. 40%, P = 0.04) were markedly improved using the low-dose CsA regimen. In multivariate analyses, low-dose CsA was strongly associated with chronic GVHD [relative hazard (RH) 2.56, P < 0.01], which decreased the risk of relapse (RH 0.46, P < 0.01) and improved the probability of survival (RH 1.84, P < 0.01). In conclusion, a low-dose CsA regimen in leukaemic recipients of HLA-identical sibling transplants increases the rate of chronic GVHD, which seems to attenuate the risk of relapse, thereby improving patient survival owing to enhanced graft-versus-leukaemia effect.

Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adoptive cell therapy approach. The European group for blood and marrow transplantation experience.

Reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HCT) allowed the existence of an allogeneic cell-mediated antitumor effect in metastatic colorectal cancer (mCRC) to be explored. We report on 39 patients with progressing mCRC treated with different RIC regimens in a multicenter clinical trial of the European Bone Marrow Transplantation Group. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (15%), and partial response (PR) in 2 (5%). All patients engrafted (median donor T cell chimerism of 90% at day +60). Transplant-related morbidities were limited. Grades II-IV acute graft-versus-host disease (aGVHD) occurred in 14 patients (35%) and chronic GVHD (cGVHD) in 9 patients (23%). Transplant-related mortality occurred in 4 patients (10%). The best tumor responses were: 1 complete response (CR) (2%), 7 PR (18 %), and 10 SD (26%), giving an overall disease control in 18 of 39 patients (46%). Allogeneic HCT after RIC is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. The study of an allogeneic cell based therapy in less advanced patients is warranted.

The allogeneic graft-versus-cancer effect.

Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.

Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation.

Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.

A Preliminary Report: Radical Surgery and Stem Cell Transplantation for the Treatment of Patients With Pancreatic Cancer.

We examined the immunologic effects of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of pancreatic ductal adenocarcinoma, a deadly disease with a median survival of 24 months for resected tumors and a 5-year survival rate of 6%. After adjuvant chemotherapy, 2 patients with resected pancreatic ductal adenocarcinoma underwent HSCT with HLA-identical sibling donors. Comparable patients who underwent radical surgery, but did not have a donor, served as controls (n=6). Both patients developed humoral and cellular (ie, HLA-A*01:01-restricted) immune responses directed against 2 novel tumor-associated antigens (TAAs), INO80E and UCLH3 after HSCT. Both TAAs were highly expressed in the original tumor tissue suggesting that HSCT promoted a clinically relevant, long-lasting cellular immune response. In contrast to untreated controls, who succumbed to progressive disease, both patients are tumor-free 9 years after diagnosis. Radical surgery combined with HSCT may cure pancreatic adenocarcinoma and change the cellular immune repertoire capable of responding to clinically and biologically relevant TAAs.

Unrelated versus related allogeneic stem cell transplantation after reduced intensity conditioning.

BACKGROUND: The use of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic stem cell transplantation (HSCT) has increased over the past five years. PATIENTS: In this study, involving 137 patients, we compared the outcome after RIC in patients receiving grafts from matched unrelated donors (MUD; n=74) and sibling donors (n=63). The MUD and sibling groups were comparable regarding diagnosis, including solid tumors and hematological malignancies, and conditioning regimens. RESULTS: Engraftment was successful in most patients (88%), with no significant difference between MUD and sibling transplants. Cytomegalovirus (CMV) infection was more common in the MUD group (65%) than in the sibling group (46%) (P=0.04). No difference in severe acute graft-versus-host disease (GVHD) was found between the groups. However, the incidence of chronic GVHD was higher after sibling transplants. This was probably due to higher donor age in this group, since this was the only significant risk factor for chronic GVHD in multivariate analysis. The incidence of transplant related mortality (TRM) was significantly higher after MUD transplantation (40%) than after sibling transplantation (16%) (P<0.01). Because relapse/disease progression was more common after sibling transplantation, there was no significant difference in overall survival between the two groups. CONCLUSION: Using unrelated donors after RIC is feasible, but it resulted in more CMV infection and increased transplant-related mortality. Survival was comparable to that of sibling transplants.

Allogeneic hematopoietic stem cell transplantation for inherited disorders: experience in a single center.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders. METHODS: We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches. RESULTS: In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease. CONCLUSION: In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.

Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.

BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). METHODS: We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. RESULTS: Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. CONCLUSION: MSC is a very promising treatment for severe steroid-resistant acute GVHD.

The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AND OBJECTIVES: Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. DESIGN AND METHODS: Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. RESULTS: The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p < 0.001), mismatch in Epstein-Barr virus (EBV) serology (p < 0.001) and splenectomy (p = 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. INTERPRETATION AND CONCLUSIONS: We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.

WITHDRAWN: Treatment with mesenchymal stromal cells does not improve long-term survival in patients with severe acute GVHD.

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Granulocyte colony-stimulating factor induced acute and chronic graft-versus-host disease.

BACKGROUND: A recent experimental study in mice shed new light on the controversy as to whether granulocyte colony-stimulating factor (G-CSF) increases graft-versus-host disease (GVHD). Total body irradiation and bone marrow were found to be prerequisites for acute GVHD. This study encouraged us to perform a retrospective clinical study. METHODS: We compared 260 patients given G-CSF prophylaxis after allogeneic hematopoietic stem-cell transplantation with 205 controls transplanted between 1993 and 2003. RESULTS: G-CSF hastened the engraftment of neutrophils, but that of platelets was delayed (P<0.0001). The proportion of acute GVHD of grades II to IV was 29% in the G-CSF group and 19% in the controls (P<0.01) and that of chronic GVHD was 54% and 43%, respectively (P=0.019). G-CSF increased acute and chronic GVHD in patients preferentially conditioned with chemotherapy. Unexpectedly, it exacerbated acute GVHD in recipients of peripheral blood stem cells and enhanced chronic GVHD in bone marrow recipients. A multivariable analysis showed that acute GVHD (hazards ratio=1.52, P=0.03) and chronic GVHD (hazards ratio=1.51, P=0.004) were associated with G-CSF. There was no significant difference between study groups regarding nonrelapse mortality, relapse, or survival. CONCLUSION: G-CSF increased acute and chronic GVHD in patients treated with chemotherapy but did not affect relapse or survival.